Drug abuse is a serious problem with both individual and societal consequences, and cocaine is a major illicit drug of abuse, with nearly 2 million cocaine users in the U.S. Despite this, there is no medication currently available for the treatment of cocaine abuse and addiction, highlighting an urgent need to examine agents for therapeutic potential in the treatment of cocaine abuse. Cocaine is known to exert its action in part by blocking the dopamine transporter that is responsible for the termination of dopamine signaling, thereby enhancing the dopamine signaling which is thought to be associated with the rewarding effects of this drug. Notably, activation of kappa opioid receptors (KOR) inhibits dopamine signaling, and thus may counteract the effects of cocaine. There is extensive evidence that KOR agonists can acutely suppress cocaine reward and self-administration. Preliminary evidence here demonstrates that a novel peptide KOR agonist suppressed cocaine reward through acute stimulation of the KOR. While this demonstrates the therapeutic value of acute KOR agonists in the treatment of cocaine abuse, repeated treatment with KOR agonists have been paradoxically shown to produce an increase in the rewarding effects of cocaine. Likewise, exposure to stress is a key factor in reinstatement of drug seeking behavior, an effect that may be mediated by activation of the KOR system by the endogenous KOR agonist dynorphin. We hypothesize that peptide KOR antagonists may therefore prevent stress-induced reinstatement. Supporting this, preliminary results here demonstrate that pretreatment with the novel peptide KOR antagonist prevented stress-induced reinstatement of cocaine conditioned place preference, suggesting that KOR antagonists could serve as effective maintenance treatments to prevent a relapse to cocaine abuse. This proposal brings together a highly synergistic team of researchers with a combination of complementary expertise to examine peptidic KOR ligands for potential treatment of cocaine abuse. The specific aims of the research are:1) to design and synthesize peptidic KOR ligands, both agonists and antagonists, with improved blood-brain barrier penetration and pharmacokinetic parameters, including metabolic stability;2) to evaluate peptide ligands in vitro for opioid receptor affinity and efficacy, potential non-opioid receptor mediated neurotoxicity, blood brain barrier transport, metabolism and pharmacokinetic properties;and 3) to evaluate selected peptide ligands in vivo, initially for opioid activity and duration of action in pain models, followed by examination in models of cocaine abuse. We expect that we will identify peptide KOR ligands that can be administered systemically to therapeutically prevent cocaine-seeking behavior.